Aniview Support Nanodrug Development Research: An LRP-1/CD44-targeted regorafenib nanodelivery system combats peritoneal metastasis of colorectal cancer through anti-angiogenic and synergistic cytotox

New progress has been made in the development of targeted nanomedicines for peritoneal metastasis of colorectal cancer.

The research team led by Zhiyong Qian from West China Hospital, Sichuan University published their findings in “Bioactive Materials” (IF = 20.3, top-tier journal).

This study provides new insights into dual receptor–mediated targeted nanoplatforms for enhancing drug accumulation and improving therapeutic efficacy against peritoneal metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, and metastatic dissemination is the primary cause of poor clinical outcomes. Among advanced-stage patients, 20%–25% develop peritoneal metastasis (PM), with a 5-year survival rate of less than 15%, highlighting the urgent need for more effective therapeutic strategies. A key pathological feature of peritoneal metastatic colorectal cancer (PMCRC) is the formation of abnormal vascular networks, which not only supply nutrients for tumor growth but also promote metastatic spread. Therefore, anti-angiogenic therapy has become an important treatment strategy, and agents such as bevacizumab and ramucirumab have demonstrated clinical efficacy.

The oral multi-target inhibitor regorafenib (REG) has attracted widespread attention due to its unique mechanism of action. REG effectively blocks the VEGF/VEGFR signaling pathway while simultaneously targeting multiple kinase receptors involved in tumor progression. It exhibits potent anti-angiogenic activity, induces tumor cell apoptosis and cell-cycle arrest, and can remodel the tumor immune microenvironment by reprogramming immunosuppressive M2 macrophages into tumoricidal M1 phenotypes. However, REG suffers from poor solubility and low permeability, which compromise systemic bioavailability and tumor drug accumulation. In addition, its off-target distribution may induce dose-limiting toxicities such as hand–foot syndrome, often requiring dose reduction or treatment interruption. Even with optimized delivery methods, achieving an effective therapeutic concentration at tumor sites remains challenging.

To overcome these limitations, nanotechnology has shown significant potential for improving drug delivery efficiency. Constructing targeted nanoplatforms based on overexpressed tumor-associated receptors is considered a key strategy for achieving precise drug delivery. Various receptor-targeting platforms have been developed, among which LRP-1 and CD44 are highly expressed in tumor cells and components of the tumor microenvironment, significantly enhancing intratumoral drug delivery. LRP-1 is highly expressed in cancer-associated fibroblasts (CAFs) and M2 tumor-associated macrophages (TAMs), while its ligand lactoferrin (LF) can mediate active targeting and macrophage phenotype remodeling. CD44 is widely expressed on tumor cell surfaces, and its ligand hyaluronic acid (HA) facilitates nanoparticle accumulation and retention within tumor tissues.

Based on these findings, the authors developed an LF-HA hybrid nanoplatform (REG@LFHA NPs) for REG delivery. The platform was constructed using the drug-loading capability of LF and its electrostatic interaction with HA, enabling dual receptor–mediated active targeting through LRP-1 and CD44 to enhance tumor accumulation. To further improve therapeutic efficacy and promote clinical translation, the study also evaluated the combined effect of this nanosystem with oxaliplatin (OxP), a first-line chemotherapeutic drug for PM-CRC. As a third-generation platinum-based agent, OxP induces tumor cell apoptosis through DNA adduct formation and serves as a core component of standard chemotherapy. However, conventional REG and OxP combination therapy is often limited by pharmacokinetic mismatch and cumulative toxicity. Preclinical models demonstrated that REG@LFHA NPs exerted antitumor effects through multiple pathways, and the therapeutic efficacy was significantly enhanced when combined with OxP. These findings verified the compatibility of the nanosystem with conventional chemotherapy and highlighted its strong translational potential for the clinical management of PM-CRC.

Experiments using Aniview

In this study, the Guangzhou Biolight Meditech Co., Ltd. AniView multimodal in vivo imaging system was used to evaluate the in vivo targeting capability and biodistribution of LFHA NPs. After intraperitoneal injection of different DiR formulations, fluorescence distribution in a mouse model of peritoneal metastasis was monitored. Compared with free DiR, both DiR@LFHA NP and DiR@LF NP exhibited stronger fluorescence signals and longer retention times in peritoneal tumor regions. Ex vivo imaging further confirmed that DiR@LFHA NP maintained the strongest fluorescence signal in tumor tissues while showing low distribution in major organs, indicating favorable tumor-targeting capability and potential safety.

(A) In vivo fluorescence imaging of tumor-bearing mice at different time points after intraperitoneal administration

(B) Average abdominal fluorescence intensity at different time points

(C) Ex vivo fluorescence imaging of isolated organs

DOI: 10.1016/j.bioactmat.2025.12.015